肿瘤细胞治疗研究
英文原题：Beyond Immunomodulatory Drugs: Next-Generation Cereblon Modulators in Multiple Myeloma.
Beyond Immunomodulatory Drugs: Next-Generation Cereblon Modulators in Multiple Myeloma.
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尽管近几十年来生存率有了显著改善，多发性骨髓瘤（MM）在很大程度上仍无法治愈，且大多数患者最终会出现复发/难治性疾病，这凸显了对新型治疗策略的需求。
尽管近几十年来生存率有了显著改善，多发性骨髓瘤（MM）在很大程度上仍无法治愈，大多数患者最终会出现复发/难治性疾病，这凸显了对新型治疗策略的需求。免疫调节药物（IMiDs）通过 cereblon 调节介导的直接抗肿瘤和免疫增强效应，改变了 MM 的治疗格局，而其刺激 T 细胞和 NK 细胞功能的能力，为与现代免疫疗法（包括双特异性抗体和嵌合抗原受体（CAR）T 细胞疗法）联合应用提供了强有力的依据。近年来，cereblon E3 连接酶调节剂（CELMoDs），如 iberdomide 和 mezigdomide，作为下一代 cereblon 靶向药物崭露头角，具有更强的效力、更深的底物降解能力，以及在来那度胺和泊马度胺耐药情况下的活性。临床研究已在新诊断和复发/难治性 MM 中，包括在重度经治患者中，显示出有前景的疗效和可控的安全性特征。与此同时，新型降解剂如 cemsidomide 已显示出令人鼓舞的初步活性，进一步拓展了 cereblon 靶向策略在 MM 中的治疗潜力。在本综述中，我们旨在总结 MM 口服治疗的演变，重点关注下一代 cereblon 调节剂和新兴 cereblon 靶向降解剂的疗效与安全性。
Despite substantial improvements in survival over recent decades, multiple myeloma (MM) remains largely incurable, and most patients ultimately experience relapsed or refractory disease, highlighting the need for novel therapeutic strategies. Immunomodulatory drugs (IMiDs) have transformed MM treatment through direct antitumor and immune-enhancing effects mediated by cereblon modulation, while their ability to stimulate T-cell and NK-cell function has provided a strong rationale for combination with modern immunotherapies, including bispecific antibodies and chimeric antigen receptor (CAR) T-cell therapies.
More recently, cereblon E3 ligase modulators (CELMoDs), such as iberdomide and mezigdomide, have emerged as next-generation cereblon-targeting agents with enhanced potency, deeper substrate degradation, and activity in lenalidomide- and pomalidomide-resistant settings. Clinical studies have demonstrated promising efficacy and manageable safety profiles across newly diagnosed and relapsed/refractory MM, including in heavily pretreated patients.
In parallel, novel degraders such as cemsidomide have shown encouraging preliminary activity, further expanding the therapeutic potential of cereblon-directed approaches in MM. In this review, we aim to summarize the evolution of oral therapies in MM, focusing on the efficacy and safety of next-generation cereblon modulators and emerging cereblon-directed degraders.
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